| AD is an age-related, progressive and irreversible neurodegenerativedisease, characterized by a gradual and permanent loss of memory and learningabilities associated with the loss of neurons. AD patients initially present mildcognitive impairment that can slowly develop serious deficits in memoryfunction and neuropsychiatric symptoms. Genetic causes of AD mainly includemutations in the APP, PS1and PS2genes. One of the most widely used ADmodels is the APP/PS1double transgenic mice. Cognitive impairment and Aβdepositions were observed in APP/PS1mouse, but most of these behaviordefects and pathological changes were occurred at the late stage of their life. Inorder to obtain an AD model that develops earlier pathological changes andcognitive impairment, we generated SAMP8-APP/PS1, a novel senescenceaccelerated APP/PS1transgenic mouse model of AD.This new model will leadto earlier onset of behavioral changes with high level of Aβ deposition in thebrain. In this study, we crossed C57APP/PS1mice with the senescenceaccelerated mice (SAMP8mice) in order to generate a new AD mouse model—SAMP8APP/PS1which would express human APP/PS1genes on anaccelerated senescence background. The SAMP APP/PS1mice were comparedwith C57wild, C57APP/PS1and SAMP8wild mice in all tests. To assess thebehavioral and other AD-related changes in SAMP8APP/PS1mice, the openfield, elevated plus maze, shuttle box and Morris water maze tests wereperformed to assess their locomotor, anxiety levels, working memory andspatial memory. Nissl staining, congo staining, immunohistochemical stainingof Aβ deposition were also conduted to investigate the neurons, amyloid-likepeptides and Aβ proteins expression of mice. Furthermore, to determine theoxidative damage of brain, we analyzed enzymatic antioxidant defense (Cu/zn-superoxide dismutase, catalase and glutathione reductase) and lipidperoxidation products malondialdehyde of the brain of mice.SAMP8APP PS1mice displayed task-dependent hyperlocomotion anddecreased of anxiety behaviours compared to C57wild type mice. Analysis ofthe shuttle box result indicated that SAMP8APP/PS1mice were impaired inlearning-memory at9months old. Water Morris maze analysis revealed thatspatial learning and memory of SAMP8APP/PS1mice were impaired at9months of age. Significant neuronal loss and amyloidosis were found in the cortex and hippocampus of SAMP8APP/PS1mice at9months of age. SAMP8APP/PS1mice show early onset and high Aβ accumulation from an age of6months. In brains of these mice, the activity of Cu/Zn-SOD, catalase andglutathione reductase were reduced and MDA levels were increased..In conclusion, SAMP8APP/PS1mice have been shown to develop manypathological features associated with Alzheimer disease, which is characterizedby severe amyloid depositions, neuronal loss, behavioral impairments anddecrease of antioxidant defense. These results demonstrate that the integrationof accelerated senescence and APP/PS1mutation exacerbate the ADprogression in SAMP8APP/PS1mice. Tau is a microtubule-associated protein that is the major component ofNFTs. These NFTs are one of the primary pathophysiological hallmarks of ADand were originally suggested to play a major role in neuronal. However,studies suggest that the toxic species may not be the mature tangles but rathera pretangle form of tau. There is increasing evidence that tau cleaved at Asp421may play a role in the oligomerization and formation of pathological pretangletau species in AD. Previous study showed that caspase activation leads to theformation of Asp421cleaved tau precedes tangle formation and indicated thatelevated levels of oxidative stress would promote the tau truncation at D421site. Taken together, we hypothesize that increasing of oxidative stress in ADbrain may induced the activation of caspase6, followed by tau truncation at siteD421.To test this hypothesis, we established the APP/PS1/tau Tg mice and giventhem oxidant or antioxidant treatments and examined the effects of oxidativestress on their spatial memory, pathological changes, caspase6expression andtau truncation by Morris water maze, nissl staining, congo staining and western blot analysis. Furthermore, activity of superoxide dismutase, catalase,glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) in brainlysates used as the oxidative biomarkers in brain were also checked. Finally,double immunohistochemistry was performed to determine if active caspase6and its substrate tau C3would be colocalizedIn the Morris water maze test, the spatial memory impairment was foundin the oxidant-treated mice. Observation of neuron number in brain revealedsignificant decreases in oxidant-treated mice compared with the antioxidant-treated mice as well as control mice. Congo red staining and Aβimmunohistology revealed that more amyloid plaques and Aβ deposition werefound in oxidant-treated mice compared with Tg and antioxidant-treated mice.We also found that oxidant-treated mice were exposed to elevated levels ofoxidative stress including the decrease of T-SOD, CAT and GSH-Px as well asthe increase of MDA in the brain tissue lysate. Western blot analysis showedthat levels of cleaved-caspase6were prominently increased in the oxidant-treated mice. Increased tau C3(tau truncation in D421site) were also observedin the oxidant-treated mice, suggesting that caspase6might promote tautruncation at site D421and cleave tau accumulated in the AD brain. Doubleimmunohistochemical revealed that increases active caspase6were colocalizedwith tau C3in oxidant-treated mice. This implies that caspase6was activated primarily in tau truncation at D421site in the AD brain.In overall, the present study suggests that oxidative stress-mediatedcaspase6activation in the process of neurodegeneration and possiblycontributes to tau truncation at D421site and neurodegeneration. The presentstudy supports the hypothesis that oxidative stress may contribute toneurondegeneration in AD possibly through activation of caspase6andtruncation of tau at D421site. |
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